海洋放线菌中亚甲基连接二聚型天然产物的发现及其生态意义

Natural products based discovery has played a significant role in human health, leading to the development of novel therapeutics and tools to understand biology. Microbial natural products, as an important part of natural products, have been the source of nearly all classes of antibiotics and a variety of anti-cancer drugs. The biosynthetic pathways of novel microbial natural products are being focused. Recent work has demonstrated that a growing number of microbial natural products involve one or more non-enzymatic steps. Some natural products take advantage of inherent reactivity to undergo dimerizations, rearrangements, or nucleophilic addition reactions to form complex metabolites. During our studies to search for new bioactive natural products from marine actinomycetes, we discovered several compounds which could utilize their high nucleophilicity to form dimers with formaldehyde via non-enzymatic reactions. This chemistry was used to generate structurally diverse of natural product families. On the basis of the previous discovery, we will continue to search for the secondary metabolites, which could react with formaldehyde to form dimers through a non-enzymatic reaction, from marine-derived actinomycetes. The ecological significance of what the actinomycetes utilize these compounds to protect themselves from formaldehyde will also be researched.

以天然产物为基础的药物发现在人类健康事业中扮演了重要角色，在促进新药研发的同时也为生物学研究提供了工具。微生物天然产物作为天然产物的重要组成部分，已经成为抗生素及抗肿瘤药物的重要来源。针对微生物天然产物生物合成过程的研究也成为热点。研究表明在许多复杂的微生物天然产物的生物合成过程中包含非酶催化的步骤，一些生物合成的产物利用自身固有的高反应活性来实现二聚、重排、亲核加成等，从而合成结构多样的新化合物。我们在对海洋放线菌活性次级代谢产物进行研究的过程中发现了多个能够利用自身的强亲核性与甲醛反应形成二聚体的化合物，并利用这一特性实现了活性化合物结构多样性的开发。本项目旨在从海洋放线菌中发现能够与甲醛发生非酶催化二聚反应的代谢产物，探讨其清除甲醛、保护微生物体自身的生态意义。

越来越多的证据表明，一些复杂微生物天然产物的形成过程中包含非酶催化的步骤，这些非酶催化反应为新骨架的构建提供了重要的驱动力。我们在研究中发现了一类甲醛参与的非酶催化反应，并且获得了亚甲基桥联二聚体。受此启发，对200株放线菌进行了筛选，获得3株能够产生可与甲醛发生二聚化反应的次级代谢产物的菌株，从中成功追踪分离到8个具有该性质的化合物，并验证了它们的二聚化反应性能。以此为基础，合成了55个衍生物，并完成了3个天然产物的合成。在研究过程中发现了7个具有较强细胞毒活性的化合物和2个强效铁络合剂，为相关药物开发提供了重要的先导化合物。我们还发现甲醛对一株放线菌的代谢具有显著调控作用，能够刺激该菌株提高甲醛捕获剂的产量，为天然甲醛捕获剂的发现提供了新的思路。此外，还发现4-羟基-6-甲基-2-吡喃酮能够有效清除水中的甲醛，为新型甲醛清除剂的开发提供了依据。相关研究成果发表在Journal of Natural Products和ACS Sustainable Chemistry & Engineering上。